Calcium phosphate cements made from (TTCP) with surface whiskers and process for preparing same

ABSTRACT

A tetracalcium phosphate (TTCP) particle for use in preparing a fast-setting, bioresorbable calcium phosphate cement is disclosed. The TTCP particle has a basic calcium phosphate whiskers on a surface thereof, the basic calcium phosphate whiskers having a Ca/P molar ratio greater than 1.33, and having a length up to about 5000 nm and a width up to about 500 nm. The basic calcium phosphate whiskers are substantially free of a hydroxyapatite phase and mainly composed of TTCP phase.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a continuation-in-part application of U.S.patent application Ser. No. 10/607,023, filed Jun. 27, 2003, which is acontinuation-in-part application of U.S. patent application Ser. No.10/414,582, filed Apr. 16, 2003, which is a continuation-in-partapplication of U.S. patent application Ser. No. 09/615,384, filed Jul.13, 2000, now abandoned, which is a continuation-in-part application ofU.S. patent application Ser. No. 09/351,912, filed Jul. 14, 1999, nowU.S. Pat. No. 6,379,453B1. The above-listed applications are commonlyassigned with the present invention and the entire contents of which areincorporated herein by reference.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to a tetracalcium phosphate (TTCP) forproducing fast-setting, bioresorbable calcium phosphate cements (CPC),and in particular, to a tetracalcium phosphate having whiskers on thesurface thereof for producing fast-setting, bioresorbable CPC having ahigh initial strength.

2. Description of the Related Art

U.S. Pat. No. 6,379,453B1 which is commonly assigned with the presentinvention discloses a process for producing a fast-setting,bioresorbable calcium phosphate cement comprising the following steps:obtaining a powder mixture from at least one calcium phosphate selectedfrom the group consisting of Ca₄(PO₄)₂O, Ca(HPO₄)₂H₂O, CaHPO₄,Ca₈H₂(PO₄)₆·5H₂O, α-Ca₃(PO4)₂, β-Ca₃(PO₄)₂, Ca₂P₂O₇, Ca₂H₂P₂O₈, whereinthe molar ratio of Ca to P in the mixture is roughly between 1 and 2;mixing the powder mixture in a phosphate-containing solution to obtain apowder/solution mixture having a concentration of less than 4 g powdermixture per ml solution; immediately heating the powder/solution mixtureto a temperature of roughly 50° C.-350° C. to obtain a powder containinguniformly distributed submicron-sized apatite crystals; and mixing theapatite crystal-containing powder in a phosphate ion-containing solutionto obtain a fast-setting, bioresorbable calcium phosphate cement.

SUMMARY OF THE INVENTION

An extensive study on the preparation of the fast-setting, bioresorbablecalcium phosphate cement disclosed in U.S. Pat. No. 6,379,453B1 has beenconducted by the same inventors and their co-workers, and found that afast-setting, bioresorbable CPC having a high initial strength can beprepared from a unique calcium phosphate, tetracalcium phosphate(Ca₄(PO₄)₂O, TTCP) particle having basic whiskers or fine crystals onthe surface thereof, wherein said basic whiskers or fine crystals have aCa/P ratio greater than 1.33. Therefore an object of the invention is toprovide such a unique TTCP particle. Another object of the presentinvention is to provide a process for preparing said unique TTCPparticle. A further object of the present invention is to provide afast-setting, bioresorbable CPC calcium phosphate cement prepared fromsaid unique TTCP particle.

The invention accomplishes the above object by providing a tetracalciumphosphate (Ca₄(PO₄)₂O, TTCP) particle having basic calcium phosphatewhiskers on a surface of said TTCP particle; said basic calciumphosphate whiskers having a length up to about 5000 nm and a width up toabout 500 urn, and preferably, a length from about 1 nm to about 2000 nmand a width from about 1 nm to about 200 rim. Said basic calciumphosphate whiskers have a Ca/P molar ratio greater than 1.33, andpreferably greater than 1.35 and less than 4.0. Said basic calciumphosphate whiskers have a non-stoichiometric chemical composition.Further, said basic calcium phosphate whiskers are substantially free ofa hydroxyapatite phase, and comprises TTCP as a major phase.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A to 1C are related to microstructure and diffraction pattern ofcalcium phosphate whiskers grown on TTCP surface according to thepresent invention, wherein (a) bright field image of whiskers; (b)electron diffraction pattern of whiskers; and (c) interpretation of thediffraction pattern.

FIG. 2 shows XRD patterns, wherein (a) TTCP without whisker treatment;(b) TTCP with whisker treatment in (NH₄)₂HPO₄ for 5 minutes; and (c) CPCprepared from whisker-treated TTCP powder immersed in Hanks' solutionfor 24 hours.

DETAILED DESCRIPTION OF THE INVENTION

The present invention discloses a process for preparing a tetracalciumphosphate (TTCP) powder comprising TTCP particles comprising basiccalcium phosphate whiskers on surfaces of said TTCP particles, saidprocess comprising the following steps:

a) mixing a TTCP powder with a whisker-inducing solution so that basiccalcium phosphate whiskers start to grow on surfaces of TTCP particlesof said TTCP powder;

b) terminating the growth of said calcium phosphate whiskers by dryingthe whisker-inducing solution in the mixture, so that said calciumphosphate whiskers have a length up to about 5000 nm and a width up toabout 500 nm, and preferably, a length from about 1 nm to about 2000 nmand a width from about 1 nm to about 200 nm, said basic calciumphosphate whiskers have a Ca/P molar ratio greater than 1.33, preferablygreater than 1.35 and less than 4.0, and said basic calcium phosphatewhiskers have a non-stoichiometric chemical composition, preferably saidbasic calcium phosphate whiskers are substantially free of ahydroxyapatite phase, and comprises TTCP as a major phase.

Optionally, at least one additive selected from the group consisting ofsodium phosphate (Na₃PO₄), disodium hydrogen phosphate (Na₂HPO₄), sodiumdihydrogen phosphate (NaH₂PO₄), disodium hydrogen phosphatedodecahydrate (Na₂HPO₄·12H₂O), disodium hydrogen phosphate heptahydrate(Na₂HPO₄·7H₂O), sodium phosphate dodecahydrate (Na₃PO₄·12H₂O),orthophosphoric acid (H₃PO₄), calcium sulfate (CaSO₄), Ca₄(PO₄)₂O,CaHPO₄·2H₂O, CaHPO₄, Ca₈H₂(PO₄)₆·5H₂O, alpha-Ca₃(PO₄)₂, beta-Ca₃(PO₄)₂,Ca₂P₂O₇, and Ca₂H₂P₂O₈, (NH₄)₃PO₄, (NH₄)₂HPO₄, and (NH₄)H₂PO₄ togetherwith said TTCP particles are mixed with the whisker-inducing solution instep a).

Optionally, said drying in step b) is carried out by heating the mixtureresulting from step a) at a temperature less than about 1000° C.Preferably, said drying in step b) comprises separating the mixtureresulting from step a) and heating the separated powder at a temperatureof about 50 to 500° C.

The heating includes (but not limited to) the conventional oven/furnaceheating, resistance heating, infrared heating, microwave heating,electron beam heating, ion beam heating, laser beam heating and plasmaheating. Preferably said heating is conducted in vacuum, inertatmosphere or air atmosphere.

The whisker-inducing solution in step a) may be an acidic aqueoussolution, a basic aqueous solution, an organic solvent or asubstantially pure water. The acidic aqueous solution may contain atleast one Ca or P source, or is free from Ca and P. The acidic aqueoussolution can be selected from the group consisting of nitric acid(HNO₃), hydrochloric acid (HCl), phosphoric acid (H₃PO₄), carbonic acid(H₂CO₃), sodium dihydrogen phosphate (NaH₂PO₄), sodium dihydrogenphosphate monohydrate, sodium dihydrogen phosphate dihydrate, potassiumdihydrogen phosphate (KH₂PO₄), ammonium dihydrogen phosphate (NH₄H₂PO₄),malic acid, acetic acid, lactic acid, citric acid, malonic acid,succinic acid, glutaric acid, tartaric acid, oxalic acid and theirmixture.

The basic aqueous solution for use as the whisker-inducing solution inthe method of the present invention may contain at least one Ca or Psource, or is substantially free from Ca and P. The basic aqueoussolution may be selected from the group consisting of ammonia, ammoniumhydroxide, alkali metal hydroxide, alkali earth hydroxide, disodiumhydrogen phosphate (Na₂HPO₄), disodium hydrogen phosphate dodecahydrate,disodium hydrogen phosphate heptahydrate, sodium phosphate dodecahydrate(Na₃PO₄·12H₂O), dipotassium hydrogen phosphate (K₂HPO₄), potassiumphosphate tribasic (K₃PO₄), diammonium hydrogen phosphate ((NH₄)₂HPO₄),ammonium phosphate trihydrate ((NH₄)₃PO₄·3H₂O), sodium bicarbonate(NaHCO₃), and their mixture.

Preferably, said whisker-inducing solution in step a) is a basic aqueoussolution. More preferably, said basic aqueous solution is a diammoniumhydrogen phosphate ((NH₄)₂HPO₄), Na₂HPO₄, or K₂HPO₄ aqueous solution. Asuitable diammonium hydrogen phosphate ((NH₄)₂HPO₄) aqueous solution hasa concentration of at least 5 wt %, preferably 10-60 wt %, based on theweight of said solution, and the mixing of said TTCP powder with thisdiammonium hydrogen phosphate ((NH₄)₂HPO₄) aqueous solution in step a)is in a ratio of less than about 10 g powder per ml solution, preferablyless than about 5 g powder per ml solution. In one of the preferredembodiment of the present invention, said concentration is about 33 wt%, and the mixing ratio is about 1 gm TTCP per 13 ml solution.

The present invention also discloses a calcium phosphate cement (CPC)powder comprising the TTCP powder of the present invention.

The following examples are intended to demonstrate the invention morefully without acting as a limitation upon its scope, since numerousmodifications and variations will be apparent to those skilled in thisart.

TTCP Preparation

The TTCP powder was fabricated in-house from the reaction of dicalciumpyrophosphate (Ca₂P₂O₇) (Sigma Chem. Co., St. Louis, Mo., USA) andcalcium carbonate (CaCO₃) (Katayama Chem. Co., Tokyo, Japan) using themethod suggested by Brown and Epstein [Journal of Research of theNational Bureau of Standards—A Physics and Chemistry 6 (1965) 69A 12].

TEM Examination

A Hitachi Model-HF2000 200 kV field emission transmission electronmicroscope (TEM) equipped with a Noran Vayager Model 1000 energydispersive spectroscopy (EDS) system was used for the study. Theaperture size for microchemical analysis (Ca/P ratio) is 15 nm.

EXAMPLE 1 Whisker-Inducing Treatment Of TTCP Particles Treated InPhosphate-Containing Basic Solution

Ca₄(PO₄)₂O (TTCP) powder as synthesized was sieved with a #325 mesh. Thesieved powder has an average particle size of about 10 gin. An aqueoussolution of diammonium hydrogen phosphate was prepared by dissolving 20g of diammonium hydrogen phosphate, (NH4)2HOP4, in 40 ml deionizedwater. The resulting solution had a pH value of 8.02. To the TTCP powderthe basic aqueous solution of diammonium hydrogen phosphate was addedaccording to the ratio of 1 gm TTCP/13 ml solution. The TTCP powder wasimmersed in the basic aqueous solution for various periods of time of 1minute, 5 minutes and 10 minutes, and filtered rapidly with a vacuumpump again. The resulting powder cake was dried in an oven at 50° C. Thedried powder was dispersed in ethanol with supersonication. A drop ofthe dispersion was dripped on a single-side carbon sieve of#325 meshhaving a diameter of 3 mm, and left dry to obtain a specimen coated witha thin carbon film for electrical conductivity for TEM examination. Themicrochemical analysis (Ca/P ratio) results often specimens (P1 to P10)for each treat time are shown in Table 1. TABLE 1 Whisker Whisker TreatCa/P width width time P1 P2 P3 P4 P5 P6 P7 P8 P9 P10 Avg. SD* (nm) (nm)1 min 1.20 1.30 1.26 1.14 1.12 1.03 1.22 1.19 1.14 1.25 1.19 0.08 <50<100 5 min 1.85 1.61 1.35 1.76 1.40 1.52 1.63 1.53 1.35 1.38 1.54 0.17<100 <300 10 min  3.81 3.20 1.78 1.74 1.80 1.38 1.61 1.81 2.01 1.63 2.080.78 <100 <300*SD = standard deviation*SD = standard deviation

FIG. 1 represents a typical microstructure of the calcium phosphatewhiskers grown on TTCP surface under such condition. FIG. 1A is abright-field image showing the whiskers are substantiallyradial-oriented and the majority of which have lengths <300 urn andwidths <100 nm; FIG. 1B is a typical electron diffraction pattern ofsuch whiskers. The dotted-ring pattern is a direct result of thediffraction of numerous nano-sized whiskers; FIG. 1C is theindexing/interpretation of the diffraction pattern, which clearly showsthat every ring matches a certain crystallographic plane of TTCP phase,indicating the whiskers have a TTCP crystal structure. The absence ofhydroxyapatite (HA) phase (100) ring (d=0.817 nm) in the diffractionpattern excludes the possibility for the whiskers to have an apatitecrystal structure under this whisker treatment condition. It also can beseen from Table 1 that basic calcium phosphate whiskers have a Ca/Pratio other than 1.67, i.e. a non-stoichiometric chemical composition.The Ca?P ratio of hydroxyapatite (HA) is 1.67. The results show thatCa/P ratio is sensitive to the process condition (in this case, treatingtime).

EXAMPLE 2 Whisker-Inducing Treatment Of TTCP Particles Treated InPhosphate-Containing Acidic Solution

The procedures of Example I were repeated except that the basic aqueoussolution was changed to 1M phosphorus acid aqueous solution having a pHof 0.8 and the immersion time was changed to 30 seconds. The results areshown in Table 2. TABLE 2 Whisker Whisker Treat Ca/P width length timeP1 P2 P3 P4 P5 P6 P7 P8 P9 P10 Avg SD* (nm) (nm) 30 sec 3.73 2.0 2.281.41 2.65 1.43 1.77 1.89 1.65 1.54 2.04 0.71 <200 <600*SD = standard deviation

EXAMPLE 3 Whisker-Inducing Treatment Of TTCP Particles Treated InPhosphate-Free Basic Solution

The procedures of Example 1 were repeated except that the basic aqueoussolution was changed to a basic aqueous NaOH solution having a pH of10.66 and the immersion time was changed to 30 seconds and 24 hours. Forthe specimens treated for 30 seconds no whisker was observed on TTCPsurface. The results for the treat time of 24 hours are shown in Table3. TABLE 3 Whisker Whisker Treat Ca/P width length time P1 P2 P3 P4 P5P6 P7 P8 P9 P10 Avg SD* (nm) (nm) 24 hr 1.90 2.19 2.80 3.40 1.47 2.051.53 1.63 1.42 2.03 2.04 0.63 <200 <600*SD = standard deviation

EXAMPLE 4 Whisker-Inducing Treatment Of TTCP Particles Treated InPhosphate-Free Acidic Solution

The procedures of Example 1 were repeated except that the basic aqueoussolution was changed to 0.1 6M HCl aqueous solution having a pH of 0.8and the immersion time was changed to 30 seconds, 10 minutes, one hourand 24 hours. For the specimens treated for 30 seconds no whisker wasobserved on TTCP surface. The results for the remaining treat times areshown in Table 4. TABLE 4 Whisker Whisker Treat Ca/P width width time P1P2 P3 P4 P5 P6 P7 P8 P9 P10 Avg. SD* (nm) (nm) 10 min 1.61 1.92 1.401.52 1.52 <50 <100  1 min 1.41 1.90 1.52 1.67 1.57 1.42 1.53 1.46 1.381.60 1.55 0.15 <100 <200 24 min 2.65 1.53 1.61 1.77 1.52 2.23 1.36 1.831.44 2.09 1.80 0.41 <200 <600*SD = standard deviation

EXAMPLE 5 Compressive Strength Of CPC Prepared From The Whisker-GrownTTCP Particles

Ca₄(PO₄)₂O (TTCP) powder as synthesized was sieved with a #325 mesh andhas an average particle size of about 10 gm. To the sieved TTCP powder aHC 1 aqueous solution having a pH of 0.8 was added according to theratio of 1 gm TTCP/13ml solution. The sieved TTCP powder was immersed inthe HC 1 solution for 12 hours, filtered rapidly and washed withdeionized water, and filtered rapidly with a vacuum pump again. Theresulting powder cake was dried in an oven at 50° C. The dried powderwas divided into halves, ground for 20 minutes and 120 minutesseparately, and combined. A setting solution of diammonium hydrogenphosphate was prepared by dissolving 20 g of diammonium hydrogenphosphate, (NH₄)₂HPO₄, in 40 ml deionized water. 100 g of the mixedground powder and 35 ml of the setting solution were well mixed to forma paste, which was then filled in molds to form specimens forcompression test. The specimens were removed from the molds 15 minutesafter the mixing, and soaked in a Hanks' solution. The soaked specimenswere removed from the Hanks' solution at various periods of soakingtime, and were immediately subjected to the compression test withoutdrying. The compression test was conducted according to a methodcommonly used in the literature. The cylindrical samples have a diameterof 6 mm and a length of 12 mm. Results: compressive strength is 27.4 MPafor the soaking time of 20 minutes, and 48 MPa for one-day soaking time.

EXAMPLE 6 Compressive Strength Of CPC Prepared From The Whisker-GrownTTCP Particles

Ca₄(PO₄)₂O (TTCP) powder as synthesized was sieved with a #325 mesh andhas an average particle size of about 10 gm. To the sieved TTCP powderthe aqueous (NH₄)₂HPO₄ solution prepared in Example 1 was addedaccording to the ratio of 1 gm TTCP/13ml solution. The sieved TTCPpowder was immersed in the (NH₄)₂HPO₄ solution for 5 minutes, filteredrapidly and washed with deionized water, and filtered rapidly with avacuum pump again. The resulting powder cake was dried in an oven at 50°C. The dried powder was ground 120 minutes to obtain a powder A. Theprocedures in Example 5 were repeated to obtain a powder B except thatthe dried powder was ground ordy for a period of 300 minutes. A mixedpowder of A and B in a ratio of 1:1 ratio was subjected to thecompression tests following the procedures recited in Example 5.Results: compressive strength is 26 MPa for the soaking time of 20minutes, and 42.8 MPa for one-day soaking time.

EXAMPLE 7 Compressive Strength Of CPC Prepared From The Whisker-GrownTTCP Particles

The procedures in Example 5 were repeated except that the HCl solutionwas changed to the aqueous (NH₄)₂HPO₄ solution prepared in Example 1 andthe soaking time was changed to 5 minutes. Results: compressive strengthis 18.6 MPa for the soaking time of 20 minutes, and 48.8 MPa for one-daysoaking time.

EXAMPLE 8 Compressive Strength Of CPC Prepared From The Whisker-GrownTTCP Particles

Ca₄(PO₄)₂O (TTCP) powder as synthesized was sieved with a #325 mesh andground for two hours. To the ground TTCP powder the powder B prepared inExample 5 was added and mixed in a ratio of 1:1. The resulting mixedpowder was subjected to the compression tests following the proceduresrecited in Example 5. Results: compressive strength is 19.7 MPa for thesoaking time of 20 minutes, and 43.6 MPa for one-day soaking time.

EXAMPLE 9 X-Ray Diffraction Of Whisker-Treated TTCP Powder And ImmersedCPC Prepared From Such TTCP

A TTCP powder was whisker-treated for 5 minutes according to the processdescribed in Example 1. X-ray diffraction (XRD) was performed using anX-ray diffractometer (Rigaku D-max IIIv, Tokyo, Japan) with Ni-filteredCuKα radiation operated at 30 kV and 20 mA at a scanning speed of1°/min. The phases were identified by matching each characteristic XRDpeak with that compiled in JCPDS files.

Results: As indicated in FIG. 2, the XRD pattern of the whisker-treatedTTCP powder (b) is substantially identical to that of TTCP assynthesized (a). The perfect match of every XRD peak position(diffraction angle) with the JCPDS data indicates that there is noadditional phase formed during the whisker treatment. 0.7 gwhisker-treated TTCP powder with 0.25 ml setting solution to form a CPCpaste. The setting solution was prepared by dissolving 20 g (NH₄)₂HPO₄in 40 ml deionized water. The CPC paste was filled in a cylindrical mold(12 mm in height and 6 mm in diameter), allowing hardening of the pasteto occur within the mold. After 15 minutes the hardened CPC sample wasremoved from the mold and immersed in a 37° C. Hanks' solution for 24hours. After removing from the Hanks' solution and drying, the CPCsample was ready for XRD analysis. After immersion in Hanks' solutionfor 24 hours, the XRD pattern (c) of the CPC shows a large amount of HAphase which has replaced TTCP as the dominant phase. At this time only asmall amount of TTCP remains. The result suggests that the CPC preparedfrom the whisker-treated TTCP powder of the invention can quicklytransform into HA (the major component of human bone), once implanted.

EXAMPLE 10 Setting Solution Prepared From (NH₄)H₂PO_(4 a)and KOH

A TTCP powder was whisker-treated for 5 minutes according to the processdescribed in Example 1. The resulting powder cake was dried in an ovenat 50° C. The dried powder was ground for 120 minutes. A settingsolution was prepared by dissolving 13.2 g (NH₄)H₂PO₄ in 40 ml deionizedwater to obtain an initial solution having a pH value of 3.72, andadding KOH to the initial solution so that the pH value was adjusted to7.5. 100 g of the ground powder and 35 ml of the setting solution werewell mixed to form a paste for 1 minute, which was then filled in moldsto form specimens for compression tests following the procedures recitedin Example 5. Results: compressive strength is 9.6 MPa for the soakingtime of 20 min.

EXAMPLE 11 Setting Solution Prepared From (NH₄)H₂PO₄ And NaOH

The procedures in Example 10 were repeated except that the KOH waschanged to NaOH and the final pH value of the setting solution was 7.8,and 20 ml of the setting solution was mixed with 100 g of the groundpowder. Results: compressive strength is 10.3 MPa for the soaking timeof 20 min.

EXAMPLE 12 Setting Solution Prepared From (NH₄)H₂PO₄ And KOH

A TTCP powder was prepared following the procedures recited in Example10. A setting solution was prepared by dissolving 7.5 g (NH₄)₂HPO₄, 2.5g NaH₂PO₄·2H₂O and 5 g K₂HPO₄ in 40 ml deionized water. The final pHvalue of the setting solution was 7.56. 100 g of the ground powder and30 ml of the setting solution were well mixed to form a paste for 1minute, which was then filled in molds to form specimens for compressiontests following the procedures recited in Example 5. Results:compressive strength is 18.0 MPa for the soaking time of 20 min.

EXAMPLE 13 Setting Solution Prepared From Na₂HPO₄·12H₂O, NaH₂PO₄·2H₂OAnd (NH₄)₂HPO₄

A TTCP powder was prepared following the procedures recited in Example10. A setting solution was prepared by dissolving 3 g Na₂HPO₄·12H₂O, 3 gNaH₂PO₄·2H₂O and 7.5 g (NH₄)2HPO₄ in 40 ml deionized water. The final pHvalue of the setting solution was 7.38. 100 g of the ground powder and30 ml of the setting solution were well mixed to form a paste for 1minute, which was then filled in molds to form specimens for compressiontests following the procedures recited in Example 5. Results:compressive strength is 20.8 MPa for the soaking time of 20 min.

EXAMPLE 14 Setting Solution Prepared From Phosphoric Acid And AmmoniaSolution

A TTCP powder was prepared following the procedures recited in Example10. A setting solution was prepared by mixing 37.68 ml of 85 wt %phosphoric acid and 100 ml deionized water, and then 73.8 ml of 28 wt %ammonia solution. The final pH value of the setting solution was 7.0.100 g of the ground powder and 30 ml of the setting solution were wellmixed to form a paste for 1 minute, which was then filled in molds toform specimens for compression tests following the procedures recited inExample 5. Results: compressive strength is 23.4 MPa for the soakingtime of 20 min.

Although a “basic” whisker can be grown on TTCP surface by immersion ina variety of solutions, the process should be carefully controlled. Forexample, when the solution contains a P source in the absence of Ca, theimmersion time should be long enough to grow a basic whisker (an“acidic” whisker is grown at the early stage due to the excess P ions inthe solution). Yet the immersion time should not be too long either toavoid the basic whisker's growing too large, that can largelydeteriorate the CPC properties.

On the other hand, when the solution does not contain P (e.g., HCl),acidic whisker is never grown on the surface of TTCP particles. All theobserved whiskers on TTCP particles at all stages are basic in nature.

In addition to Ca/P ratio, the growth rate of a basic whisker is alsosensitive to such process parameters as the type, pH, temperature andion concentrations of the solution, to name a few.

Although the present invention has been described with reference tospecific details of certain embodiments thereof, it is not intended thatsuch details should be regarded as limitations upon the scope of theinvention except as and to the extent that they are included in theaccompanying claims. Many modifications and variations are possible inlight of the above disclosure.

1-18. (canceled)
 19. A calcium phosphate cement made by the processcomprising: contacting tetracalcium phosphate (TTCP) particles with awhisker-inducing liquid for a period of time such that whiskers having alength of up to about 5000 nm and a width of up to about 500 nm form onthe surface of at least a portion of the TTCP particles, wherein thewhiskers comprise basic calcium phosphate comprising TTCP as the majorphase, and wherein the Ca/P molar ratio of the basic calcium phosphatecomprising the whiskers is at least about 1.33; substantially separatingthe TTCP particles from the whisker-inducing liquid; and contacting theTTCP particles with a setting solution.
 20. The method of claim 19,wherein the whisker inducing liquid comprises an acidic solution. 21.The method of claim 19, wherein the whisker inducing liquid comprisesnitric acid (HNO₃), hydrochloric acid (HCl), phosphoric acid (H₃PO₄),carbonic acid (H₂CO₃), sodium dihydrogen phosphate (NaH₂PO₄), sodiumdihydrogen phosphate monohydrate, sodium dihydrogen phosphate dihydrate,potassium dihydrogen phosphate (KH₂PO₄), ammonium dihydrogen phosphate(NH₄H₂PO₄), malic acid, acetic acid, lactic acid, citric acid, malonicacid, succinic acid, glutaric acid, tartaric acid, oxalic acid andmixtures thereof.
 22. The method of claim 19, wherein the whiskerinducing liquid comprises a source of phosphate ions.
 23. The method ofclaim 19, wherein the whisker inducing liquid comprises phosphoric acid.24. The method of claim 19, wherein the whisker inducing liquidcomprises hydrochloric acid.
 25. The method of claim 19, wherein thewhisker inducing liquid comprises a basic solution.
 26. The method ofclaim 19, wherein the whisker inducing liquid comprises ammonia,ammonium hydroxide, alkali metal hydroxide, alkali earth hydroxide,disodium hydrogen phosphate (Na₂HPO₄), disodium hydrogen phosphatedodecahydrate, disodium hydrogen phosphate heptahydrate, sodiumphosphate dodecahydrate (Na₃PO₄·12H₂O), dipotassium hydrogen phosphate(K₂HPO₄), potassium phosphate tribasic (K₃PO₄), diammonium hydrogenphosphate ((NH₄)₂HPO₄), ammonium phosphate trihydrate ((NH₄)₃PO₄·3H₂O),sodium bicarbonate (NaHCO₃), or mixtures thereof.
 27. The method ofclaim 19, wherein the whisker inducing liquid comprises a source ofammonium ions.
 28. The method of claim 19, wherein the whisker inducingliquid comprises a source of potassium ions.
 29. The method of claim 19,wherein the whisker inducing liquid comprises a source of sodium ions.30. The method of claim 19, wherein the whisker inducing liquidcomprises diammonium hydrogen phosphate.
 31. The method of claim 19,wherein the whisker inducing liquid comprises sodium hydroxide.
 32. Themethod of claim 19, wherein the ratio of TTCP particles to whiskerinducing liquid is less than about 10 g/ml.
 33. The method of claim 19,wherein the ratio of TTCP particles to whisker inducing liquid is lessthan about 5 g/ml.
 34. The method of claim 19, wherein the TTCPparticles are contacted with the whisker inducing liquid for up to about24 hours.
 35. The method of claim 19, wherein the TTCP particles arecontacted with the whisker inducing liquid for between about 1 minute toabout 10 minutes.
 36. The method of claim 19, further comprising mixingan additive with the TTCP particles, wherein contacting the TTCPparticles with the whisker inducing liquid comprises contacting themixture of TTCP particles and the additive with the whisker inducingliquid.
 37. The method of claim 36, wherein the additive comprisessodium phosphate (Na₃PO₄), disodium hydrogen phosphate (Na₂HPO₄), sodiumdihydrogen phosphate (NaH₂PO₄), disodium hydrogen phosphatedodecahydrate (Na₂HPO₄·12H₂O), disodium hydrogen phosphate heptahydrate(Na₂HPO₄·7H₂O), sodium phosphate dodecahydrate (Na₃PO4·12H₂O),orthophosphoric acid (H₃PO₄), calcium sulfate (CaSO₄), Ca₄(PO₄)₂O,CaHPO₄·2H₂O, CaHPO₄, Ca₈H₂(PO₄)₆·5H₂O, alpha-Ca₃(PO₄)₂, beta-Ca₃(PO₄)₂,Ca₂P₂O₇, and Ca₂H₂P₂O₈, (NH₄)₃PO₄, (NH₄)2HPO₄, and (NH₄)H₂PO₄, ormixtures thereof.
 38. The method of claim 19, wherein the pH of thesetting solution is between about 7.0 to about 7.8.
 39. The method ofclaim 19, wherein separating the TTCP particles from thewhisker-inducing liquid comprises heating the TTCP particles to atemperature of up to about 1000° C.
 40. The method of claim 19, whereinseparating the TTCP particles from the whisker-inducing liquid comprisesheating the TTCP particles to a temperature of between about 50° C. toabout 500° C.